Rare mutations in XRCC2 increase the risk of breast cancer

D. J. Park, Fabienne Lesueur, T. Nguyen-Dumont, Maroulio Pertesi, Fabrice Odefrey, Fleur Hammet, Susan L Neuhausen, Esther M. John, Irene L Andrulis, Mary Beth Terry, Thomas M Daly, Saundra S. Buys, Florence L. Le Calvez-Kelm, Andrew Lonie, Bernard J. Pope, Helen Tsimiklis, Catherine Voegele, F. M. Hilbers, N. Hoogerbrugge, A. BarrosoAna Osorio, G. G. Giles, Peter Devilee, J. Benitez, J. L. Hopper, Sean V. Tavtigian, David E. Goldgar, M. C. Southey

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143 Citations (Scopus)


An exome-sequencing study of families with multiple breast-cancer-affected individuals identified two families with XRCC2 mutations, one with a protein-truncating mutation and one with a probably deleterious missense mutation. We performed a population-based case-control mutation-screening study that identified six probably pathogenic coding variants in 1,308 cases with early-onset breast cancer and no variants in 1,120 controls (the severity grading was p < 0.02). We also performed additional mutation screening in 689 multiple-case families. We identified ten breast-cancer-affected families with protein-truncating or probably deleterious rare missense variants in XRCC2. Our identification of XRCC2 as a breast cancer susceptibility gene thus increases the proportion of breast cancers that are associated with homologous recombination-DNA-repair dysfunction and Fanconi anemia and could therefore benefit from specific targeted treatments such as PARP (poly ADP ribose polymerase) inhibitors. This study demonstrates the power of massively parallel sequencing for discovering susceptibility genes for common, complex diseases.

Original languageEnglish
Pages (from-to)734-739
Number of pages6
JournalAmerican Journal of Human Genetics
Issue number4
Publication statusPublished - 6 Apr 2012
Externally publishedYes

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